tbuckley/cabot-search huggingface dataset:
Subcutaneous epcoritamab with rituximab + lenalidomide (R<sup>2</sup>) in patients (pts) with relapsed or refractory (R/R) follicular lymphoma (FL): Update from phase 1/2 trial.
Authors: Lorenzo Falchi, Sirpa Leppä, Bjorn E. Wahlin, Marcel Nijland, Jacob Haaber Christensen, Sven De Vos, Harald Holte, Kim M. Linton, Aqeel Abbas, Liwei Wang, Minh Dinh, Brian Elliott, David Belada
Journal: Journal of Clinical Oncology (2022)

7524 Background: R/R FL is associated with poor prognosis and less frequent, shorter responses with each line of treatment (Tx). Although R 2 is an effective regimen in R/R FL with an acceptable safety profile, FL remains incurable; thus, better Tx options are needed. Subcutaneous epcoritamab is a bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on malignant B cells. In the dose-escalation part of the phase 1/2 EPCORE NHL-1 trial, single-agent epcoritamab (0.76–48 mg) resulted in an overall response rate of 90% and a complete response rate of 50% in R/R FL. The distinct mechanisms of action of epcoritamab and R 2 may combine to increase antitumor response, with generally non-overlapping toxicity profiles. We present updated data for epcoritamab with R 2 in R/R FL (EPCORE NHL-2 arm 2; NCT04663347). Methods: Adults with R/R CD20 + FL received epcoritamab + R 2 for 12 cycles (C) of 28 d; epcoritamab was administered at 24 or 48 mg in dose escalation and 48 mg in expansion. During C1, step-up epcoritamab dosing and corticosteroids were required to mitigate CRS. Response was assessed by PET-CT. The epcoritamab regimen for these pts was: Q1W, C1–3; Q2W, C4–9; Q4W, C≥10 up to 2 y. Results: As of December 1, 2021, 30 pts (median age, 68 y) had received epcoritamab + R 2 (24 mg, n=3; 48 mg, n=27), 21 pts (70%) had stage IV disease, and 20 pts (67%) had FLIPI scores 3–5. Median (range) number of prior lines of therapy was 1 (1–5), 30% had primary refractory disease, and 40% had disease progression within 24 mo after starting first-line Tx (20% within 24 mo after starting immunochemotherapy). At a median (range) follow-up of 5.1 mo (0.8–12.3), 25 pts (83%) remained on Tx; 5 pts discontinued Tx due to progression (n=2), AEs (n=2), or consent withdrawal (n=1). Common Tx-emergent AEs (TEAEs) of any grade (G) included infections (57%), injection-site reactions (50%), constipation (37%), fatigue (37%), and neutropenia (37%). CRS was seen in 15 pts (50%; G1/2 43%, G3 7%), with most events in C1. All CRS events resolved with standard management, including tocilizumab in 3 pts, and 1 pt discontinued Tx due to CRS. One pt experienced G2 ICANS. No fatal TEAEs occurred. Antitumor activity is shown in the Table. As of the data cut, all responders remained in response, with the longest duration of response being 7.0+ mo and ongoing. Conclusions: Subcutaneous epcoritamab+ R 2 exhibits promising efficacy, including a high CMR rate, in pts with R/R FL. The safety profile was consistent with prior data, and CRS events were generally low grade and in C1. Updated data with an additional 30 pts will be presented. Clinical trial information: NCT04663347. [Table: see text]
A systemic review and meta-analysis of FOLFIRINOX vs gemcitabine plus nab-paclitaxel in the neoadjuvant treatment of localized pancreatic cancer.
Authors: Zainab Fatima, Ammar Alhabhbeh, Mohammad Darweesh, Hisham Laswi, Sukesh Manthri
Journal: Journal of Clinical Oncology (2022)

e16272 Background: Localized pancreatic adenocarcinoma (PDAC) includes resectable, borderline resectable, and locally advanced cancers. In potentially resectable pancreatic cancer, the role of neoadjuvant therapy is evolving and guidelines from expert groups are conflicting. Although limited, randomized trials have shown that neoadjuvant chemotherapy (NCT) can provide survival benefits in patients with localized PDAC. Studies have compared FOLFIRINOX (FFN) with Gemcitabine plus nab-Paclitaxel (G-nP) as first-line NCT for PDAC, but no consensus has been established. As a result, we performed an updated meta-analysis to assess the difference in overall survival between two chemotherapy regimens. Methods: PubMed, EMBASE, and Cochrane databases were systematically reviewed from inception to December 2021 to identify studies comparing FFN with G-nP in the neoadjuvant settings for localized PDAC. The primary outcome was the overall survival of patients and secondary endpoints were RECIST partial or complete response, resection rate and R0 resection. The effectiveness of FOLFIRINOX and G-nP in terms of overall survival in patients with localized PDAC was compared using hazard ratios (HR) and 95% confidence intervals (CI). In addition, the heterogeneity of the studies was evaluated using Cochrane's Q test of heterogeneity and the I 2 statistic. Pooled analysis of HR was performed with Stata 17 METAN using random effect model and P of 0.05 was considered statistically significant. Results: We identified 10 studies that met our inclusion criteria. All studies were retrospective and 5 of them were carried out in the United States. The total numbers of patients preoperatively treated with FOLFIRINOX versus G-nP were 988 and 719, respectively. In this meta-analysis compared to G-nP, neoadjuvant FFN was associated with significant prolonged overall survival (HR = 0.72, 95% CI: 0.63–0.82, P &lt; 0.001). FFN group had a significantly higher RECIST partial and complete response rate than the G-nP group, with an OR of 1.65 (95 % CI 1.02-2.68, p = 0.04). For resection rate and R0 resection, FFN group had ORs of 1.65 (95% CI 0.94-2.90, p = 0.08) and 1.91 (95% CI 0.95-3.81, P = 0.07) respectively, both outcomes were statistically insignificant. Conclusions: Results of our meta-analysis show that for localized pancreatic cancer, neoadjuvant treatment with FFN was associated with better survival than G-nP. One limitation to our current study was that all included studies were designed retrospectively. Further randomized clinical trials are needed to explore the ideal neoadjuvant chemotherapy for PDAC.[Table: see text]
Calcium, contraction, and hemodynamic alterations induced by arrhythmogenic drugs in the zebrafish larvae
Authors: J Salgado-Almario, M Vicente, Y Molina, A Martinez-Sielva, P Vincent, B Domingo, J Llopis
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): MCIN/AEI/ 10.13039/501100011033 and “ERDF A way of making Europe” by the European Union Background Ca2+ ion is pivotal in excitation-contraction coupling. The dysregulation of Ca2+ fluxes is at the core of inherited and acquired arrhythmias. In recent years zebrafish have become an attractive vertebrate model to study heart development, cardiotoxicity, and heart diseases. We recently reported that the transgenic zebrafish line Tg(myl7:Twitch-4) expressing the ratiometric Ca2+ indicator Twitch-4 in the heart, allowed imaging Ca2+ transients (CaT) simultaneously with heart contraction in zebrafish larvae, thus maintaining the physiological mechano-electrical feedback. Purpose This study aimed to detect subtle disturbances in Ca2+ cycling, contractility, and hemodynamics induced by arrhythmogenic drugs in zebrafish larvae. Methods We have used the zebrafish transgenic line Tg(myl7:Twitch-4) and a custom software to acquire and analyze fluorescence emission ratio images of the heart. Larvae of 3- and 5-days post-fertilization (dpf) were incubated with arrhythmogenic drugs, and their effects on the systolic and diastolic Ca2+ and the CaT amplitude in the atrium and ventricle were determined. As the ventricular diameter was assessed in the same fluorescence images, a simultaneous, real-time, measurement of contraction correlated with Ca2+ was obtained. The systolic and diastolic areas, measured independently, were used to estimate hemodynamic parameters. Results Dofetilide caused time-dependent bradycardia and ultimately a 2:1 arrhythmia in 3 and 5 dpf larvae, with an increase in the CaT amplitude. the ejection fraction and the stroke volume increased, but the cardiac output decreased due to the low heart rate (2:1 arrhythmia). The T-type Ca2+ channel antagonist ML218 induced bradycardia and decreased systolic and diastolic Ca2+ levels in 3 dpf larvae, but the CaT amplitude did not change. Interestingly, some larvae (3 out of 14) displayed a progressive lengthening of the time between the start of atrial and ventricular CaT, analogous to increased PR interval of the electrocardiogram, until a ventricular systole failed. This is reminiscent of a second-degree atrioventricular block in humans. At higher ML218 concentration, a 2:1 arrhythmia was observed and increased ventricular CaT amplitude in all larvae. Conclusions We characterized Ca2+ changes induced by arrhythmogenic drugs and correlated them with contractility and hemodynamic parameters. The zebrafish line Tg(myl7:Twitch-4) allowed investigating drug-induced arrhythmias in this animal model with unprecedented detail. This transgenic line will serve to screen cardiotoxicity during drug development and to study conduction and rhythm defects in zebrafish, and their correlation with human disease.
Unravelling sex-dependent mechanisms in calcific aortic valve stenosis
Authors: D Moschetta, I Massaiu, V Valerio, M Bozzi, V Myasoedova, P Poggio
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Italian Ministry of Health Background Calcific aortic valve stenosis (CAVS) is the most common heart valve disease that affects 3% of the population. CAVS is a progressive, multifactorial disorder driven by several cellular and molecular pathological processes. Currently, there is no pharmacological therapy able to prevent CAVS progression. Little is known about the sex-related difference in molecular mechanisms. Recent studies reported that men showed a higher aortic valve calcium load than women, which in turn, developed more fibrosis in the stenotic aortic valve leaflets. Hence, it has been hypothesized that the mechanisms underlying CAVS progression could be different between the two sexes. Purpose To investigate sex-differences in CAVS molecular pathways, finding new sex-related pharmacological targets. Methods Valve interstitial cells (VIC) were isolated from 26 patients who underwent aortic valve replacement for aortic valve stenosis. RNA, extracted from VICs, was sequenced by third generation sequencing technology. We performed pro-fibrotic (TGFβ) treatment for 5 days and we evaluated soluble collagen expression by a colorimetric assay and αSMA expression by western blot. We evaluated extracellular calcium extent by a colorimetric assay on VICs exposed to pro-calcific (inorganic phosphate) medium for 7 days. We assessed the mitochondrial damage with mitoSOX staining by Imagestream. Results The gene expression analysis from sequenced VICs revealed 65 genes upregulated in men and 89 genes upregulated in women. The functional analysis showed that the TGFβ signaling resulted enriched in woman VICs, while the mitochondrial related genes were upregulated in man VICs. Only woman VICs secreted higher amount of collagen under TGFβ treatment respect to the untreated (1.22±0.03 fold change (FC) vs. untreated, p&amp;lt;0.001). αSMA expression (marker of VICs activation) was significantly higher both in men and women exposed to different concentrations of TGFβ (TGFβ 5ng/ml: 1.88±0.34 in men and 2.66±0.32 in women, FC vs. untreated, p=0.003 and p&amp;lt;0.0001, respectively; TGFβ 10ng/ml: 2.96±0.55 in men and 2.16±0.35 in women, FC vs. untreated, p=0.0003 and p=0.0006, respectively). The calcification potential of VICs exposed to pro-calcific medium was higher in men than in women (8.23±0.45 vs. 4.69±0.59 FC vs. untreated, respectively, p&amp;lt;0.0001). The mitochondrial superoxide formation in man VICs was higher than in woman VICs at steady state (51.0±2.1% vs. 29.5±0.9% of positive cells, respectively, p&amp;lt;0.0001) Conclusion CAVS progression seems to be driven by sex-dependent molecular pathways activation. In particular, pro-fibrotic pathways are upregulated in women, while pro-calcific pathways and mitochondrial damage in men. Our data pave the way to sex-dependent pharmacological target research, aiming to treat CAVS patients.
Coordinating a multi-disciplinary team to reduce financial hardship from cancer: A clinic-based financial navigator approach.
Authors: Matthew P. Banegas, Blake W. Locher, Leah Tuzzio, Jennifer L. Schneider, Jennifer S. Rivelli, Nora B. Henrikson
Journal: Journal of Clinical Oncology (2022)

e13527 Background: As efforts to reduce financial hardship within oncology settings increase, development of multidisciplinary approaches based on principles of care coordination – effective communication, shared goals, role clarity, handoff – are essential. Cancer Financial Experiences (CAFÉ) is a randomized controlled trial [NCT05018000] of a financial navigation intervention in two regions of Kaiser Permanente. Our objective was to develop workflows for CAFÉ Financial Navigators (CNs) to provide navigation to trial participants by engaging a multidisciplinary team. Methods: Workflows are based on our conceptual framework of unique care pathways to address financial concerns among cancer patients: resolving acute financial needs; planning for out of pocket (OOP) costs; and making cost-informed care decisions. Influenced by user-centered design, we collected multi-stakeholder perspectives through interviews with approximately 39 staff from 15 departments between 2019-2021 including clinicians (e.g. physicians, nurses, social workers), health care staff (e.g. case managers, patient navigators) and operations/business staff (e.g. business operations analysts, financial counselors). Topics included the current state; existing organizational and informal relationships between operations units; and opportunities for improvement relative to current evidence on patient needs for cancer-related financial navigation. Results: We identified several opportunities to create or enhance workflows to provide financial navigation for oncology patients. We also identified organizational barriers that require further work (e.g., providing detailed oncology-specific fee estimates for treatment and OOP costs). Workflows centered the CN as a primary contact for patients to facilitate engagement with services and ensure effective, consistent connections between patients and care delivery and operations units. We developed (1) cost coordination maps outlining the healthcare team member points of contact within departments and sequence of contacts, for addressing each financial pathway and (2) resource directories that detail the unique financial needs, contact information and role for CNs. We maintained these strategic relationships throughout the trial to serve participants and support sustainability. Conclusions: Our multi-stakeholder strategy aligns clinical and healthcare operations workflows to optimize patient experience and outcomes to reduce financial hardship from cancer. Our work suggests research teams can facilitate process improvement within care delivery settings. However, barriers to certain financial navigation processes remain, reflecting future research needs. An oncology-specific financial navigation model supported by multidisciplinary workflows is key to addressing financial hardship from cancer.
Whole-genome and transcriptome analysis enhances precision cancer treatment options
Authors: E. Pleasance, A. Bohm, L.M. Williamson, J.M.T. Nelson, Y. Shen, M. Bonakdar, E. Titmuss, V. Csizmok, K. Wee, S. Hosseinzadeh, C.J. Grisdale, C. Reisle, G.A. Taylor, E. Lewis, M.R. Jones, D. Bleile, S. Sadeghi, W. Zhang, A. Davies, B. Pellegrini, T. Wong, R. Bowlby, S.K. Chan, K.L. Mungall, E. Chuah, A.J. Mungall, R.A. Moore, Y. Zhao, B. Deol, A. Fisic, A. Fok, D.A. Regier, D. Weymann, D.F. Schaeffer, S. Young, S. Yip, K. Schrader, N. Levasseur, S.K. Taylor, X. Feng, A. Tinker, K.J. Savage, S. Chia, K. Gelmon, S. Sun, H. Lim, D.J. Renouf, S.J.M. Jones, M.A. Marra, J. Laskin
Journal: Annals of Oncology (2022)

Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data provided by whole-genome and transcriptome sequencing and analysis (WGTA) present an opportunity to align a much larger proportion of patients to therapies.Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected.Clinically actionable targets were identified for 83% of patients, of which 37% of patients received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, poly-ADP ribose polymerase inhibitors and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%) and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies.Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.
Disparities in NCI and nonprofit organization funding and effect on cancers with high incidence rates among Black patients and mortality rates.
Authors: Suneel Deepak Kamath, Yanwen Chen
Journal: Journal of Clinical Oncology (2022)

1509 Background: National Cancer Institute (NCI) and nonprofit organization (NPO) funding is critical for research and advocacy, but may not be equitable across cancers or racial and ethnic groups. Methods: This study evaluated funding from the NCI and NPOs supporting lung, breast, colorectal, pancreatic, hepatobiliary, prostate, ovarian, cervical and endometrial cancers, leukemia, lymphoma and melanoma from 2015-2018. The primary objectives were to assess for disparities in NCI and NPO funding across different cancers compared to their incidence and mortality and their incidence rates across age, racial and ethnic groups. We also investigated if underfunding correlates with fewer clinical trials. Correlations between NCI and NPO funding for each cancer and its incidence, mortality and number of clinical trials were analyzed using scatter plots and Pearson correlation coefficients (PCCs). Results: Diseases with the largest combined NCI and NPO funding were breast cancer ($3.75 billion) and leukemia ($1.99 billion). Those with the least funding were endometrial ($94 million), cervical ($292 million), and hepatobiliary cancers ($348 million). Disease-specific funding correlated well with incidence, but correlated poorly with mortality (PCCs: 0.74, p = 0.006 and 0.30, p = 0.346, respectively). Breast cancer, leukemia and lymphoma were consistently well-funded, while colorectal, lung, hepatobiliary and uterine cancers were consistently underfunded. These data are summarized in the Table. NCI and NPO funding increased proportionately as incidence increased for White patients (PCC: 0.73, p = 0.007), Hispanic patients (PCC: 0.66, p = 0.02), Asian/Pacific Islanders (PCC: 0.77, p = 0.003) and Native Americans and Alaskans (PCC: 0.72, p = 0.008) while cancers with higher incidence in the Black population were underfunded (PCC: 0.52, p = 0.08). The amount of combined NCI and NPO funding for a particular cancer correlated strongly with the number of clinical trials for that disease (PCC: 0.91, p &lt; 0.0001). Conclusions: Many cancers with high incidence and mortality are underfunded, including those with higher incidence among Black patients. Underfunding strongly correlates with fewer clinical trials, which could impede future advances in underfunded cancers. [Table: see text]
DIPG-02. Role of a Bevacizumab-based regime in the treatment of children with diffuse intrinsic pontine glioma (DIPG): a systematic review
Authors: Mia Evans, Ria Gill, Kim Bull
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is an aggressive paediatric brainstem tumour. There are no effective treatments and median survival is 11.2 months, therefore maintaining quality of life (QOL) is a priority for many families. Bevacizumab, an anti-VEGF IgG antibody, has the potential to improve QOL and survival in DIPG, but has never been evaluated systematically. AIM: To collate the evidence and assess the role of this drug, in the treatment of DIPG. METHODS: MEDLINE, EMBASE, Scopus and Web of Science were searched for relevant studies using terms developed from PICO criteria, including alternatives for Bevacizumab and DIPG. One reviewer screened titles and abstracts, then two reviewers screened full texts. Data were extracted into tables and study quality assessed using MINORS and JBI tools. RESULTS: Searching revealed 1,001 papers; after deduplication 851 remained. After screening of titles and abstracts, 28 full texts were screened, resulting in the inclusion of 11 studies. All studies evaluated more than one outcome. Four studies reported a median overall survival longer than historical data, however, two determined no significant impact. Five studies reported a radiological response in a proportion of participants and two reported no response. Three studies evaluating clinical response, reported improvement in a proportion of patients. Three studies evaluating QOL reported stability or improvement. Four studies evaluating steroid use reported reductions in the proportion of patients receiving steroids. In the treatment of radiation necrosis, Bevacizumab led to clinical improvement in 6/12 patients in 2 studies and permitted a reduction in steroid use in the majority of patients. CONCLUSION: Insufficient evidence means the role of Bevacizumab in the treatment of DIPG is unclear. However, Bevacizumab may be beneficial to some patients. The review highlights the need for further research in this area, particularly randomised controlled trials. More effective therapies are desperately needed.
Intraarticularly injectable silk hydrogel microspheres with enhanced mechanical and structural stability to attenuate osteoarthritis
Authors: Tao Wang, Yuqi Li, Jian Liu, Yan Fang, Wenjun Guo, Yu Liu, Xiangyu Li, Gang Li, Xiuli Wang, Zhaozhu Zheng, Xiaoqin Wang, David L. Kaplan
Journal: Biomaterials (2022)
Silk sericin patches delivering miRNA-29-enriched extracellular vesicles-decorated myoblasts (SPEED) enhances regeneration and functional repair after severe skeletal muscle injury
Authors: Yu Song, Miaomiao Li, Shijun Lei, Lu Hao, Qiying Lv, Miaodeng Liu, Guobin Wang, Zheng Wang, Xiaobing Fu, Lin Wang
Journal: Biomaterials (2022)